An excess of the activity of the matrix metalloproteinases (MMPs) over the tissue inhibitor of metalloproteinases (TIMP) available to "mop up" the activity occurs at the sites of degradation of articular cartilage in arthritis patients and at sites of tumor invasion and metastasis in cancer patients. TIMPs and small synthetic inhibitors of MMPs can reduce the extent of this cartilage breakdown. TIMPs have also been demonstrated to suppress proliferation, invasion, and metastasis of aggressive tumors. Very little is known about how TIMPs inhibit MMPs such as stromelysin. Atomic-resolution structural information about the TIMP-1/stromelysin complex would aid development of better inhibitors of MMPs which mimic TIMP but are easier to deliver that TIMP. Prerequisites for generating an NMR structure of the TIMP-1/stromelysin complex relevant to arthritis include: 1) the tertiary structure of the catalytic domain of stromelysin, 2) the tertiary structure of the inhibitory domain of TIMP-1, and 3) the faces of each which embrace one another. The P.I. recently determined the tertiary structure of the stromelysin catalytic domain in solution by NMR. A tertiary structure of at least medium resolution is needed for TIMP-1. We have begun to determine such a structure of the inhibitory domain of TIMP-1 in solution. The "footprint" TIMP leaves upon stromelysin, i.e., the surface of stromelysin perturbed by TIMP binding, will be determined by established NMR methods. The footprint stromelysin leaves upon TIMP will also be determined. This work should enable us in the future to dock the protease and inhibitor using known NMR methods. The structural insight into the stromelysin-TIMP complex will provide new ideas for designing TIMP-mimicking drugs.